Discovery of pentacyclic compounds as potent inhibitors of hepatitis C virus NS5B RNA polymerase

被引：42

作者：

Habermann, Joerg ^{[1
]}

Capito, Elena ^{[1
]}

Ferreira, Maria del Rosario Rico ^{[1
]}

Koch, Uwe ^{[1
]}

Narjes, Frank ^{[1
]}

机构：

[1] Merck Res Labs, IRBM P Angeletti SpA, Dept Med Chem, I-00040 Pomezia, Rome, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 03期

关键词：

HCV; HCV NS5B polymerase inhibitor; Pauson-Khand reaction; 1,3]-Dipolar cycloaddition; NONSTABILIZED AZOMETHINE YLIDES; STEREOSELECTIVE-SYNTHESIS; NONNUCLEOSIDE INHIBITORS; ALLOSTERIC INHIBITORS; PROTEIN-BINDING; RECENT PROGRESS; AMINO-ACIDS; CYCLOADDITION; BENZIMIDAZOLE; ENTRY;

D O I：

10.1016/j.bmcl.2008.12.039

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report a new series of inhibitors for hepatitis C virus NS5B RNA polymerase containing a constrained pentacyclic scaffold. Our SAR studies led to the identification of hexahydroindolo[2,1-a] pyrrolo[3,2-d][2] benzazepines exposing basic groups. The compounds displayed a high activity in the enzyme assay and displayed good activity in the cell-based (replicon) assay in the presence of serum proteins. (c) 2008 Elsevier Ltd. All rights reserved.

引用

页码：633 / 638

页数：6

共 43 条

[1]

*ADV CHEM DEV INC, CALC PHYS PROP WER D

[2]

Beaulieu PL, 2007, CURR OPIN INVEST DR, V8, P614

[3]

Beaulieu PL, 2006, CURR OPIN DRUG DISC, V9, P618

[4] Non-nucleoside inhibitors of the hepatitis C virus NS5B polymerase:: discovery of benzimidazole 5-carboxylic amide derivatives with low-nanomolar potency [J].

Beaulieu, PL ;

Bös, M ;

Bousquet, Y ;

DeRoy, P ;

Fazal, G ;

Gauthier, J ;

Gillard, J ;

Goulet, S ;

McKercher, G ;

Poupart, MA ;

Valois, S ;

Kukolj, G .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (04) :967-971

[5] DESIGN AND SYNTHESIS OF INTRAMOLECULAR ION-PAIRING CIS-BICYCLO[4.4.0]DECANE (CIS-DECALIN) AMINO-ACIDS - CONFORMATION-BASED PROBES OF ELECTROSTATIC INTERACTIONS IN WATER [J].

BEESON, C ;

DIX, TA .

JOURNAL OF ORGANIC CHEMISTRY, 1992, 57 (16) :4386-4394

[6] Protein binding in antiretroviral therapies [J].

Boffito, M ;

Back, DJ ;

Blaschke, TF ;

Rowland, M ;

Bertz, RJ ;

Gerber, JG ;

Miller, V .

AIDS RESEARCH AND HUMAN RETROVIRUSES, 2003, 19 (09) :825-835

[7]

Capito E., 2007, Pat, Patent No. [2007129119, 2007/129119]

[8] The scientific challenge of hepatitis C [J].

Cohen, J .

SCIENCE, 1999, 285 (5424) :26-30

[9] Intramolecular dipolar cycloaddition reactions of azomethine ylides [J].

Coldham, I ;

Hufton, R .

CHEMICAL REVIEWS, 2005, 105 (07) :2765-2809

[10] Advances in the development of new therapeutic agents targeting the NS34A serine protease or the NS5B RNA-dependent RNA polymerase of the hepatitis C virus [J].

De Francesco, Raffaele ;

Carfi, Andrea .

ADVANCED DRUG DELIVERY REVIEWS, 2007, 59 (12) :1242-1262

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